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Functional characterization of a novel class of morantel-sensitive acetylcholine receptors in nematodes

Functional characterization of a novel class of morantel-sensitive acetylcholine receptors in nematodes
Functional characterization of a novel class of morantel-sensitive acetylcholine receptors in nematodes
The control of parasitic nematode infections in humans, livestock and companion animals is critically dependent on anthelmintic treatment. However, the indiscriminate use of anthelmintic drugs has inevitably led to the selection of resistant parasites. In this respect there is currently an urgent need to increase our knowledge of the mode of action of available anthelmintics as well as to identify novel targets for the development of next generation anthelmintic compounds. In the present study we report the functional and pharmacological characterization of a novel subtype of nematode acetylcholine-gated ion channel in two distantly related parasitic nematode species: Haemonchus contortus and Parascaris equorum. Using the Xenopus laevis oocyte as an expression system, we showed that these receptors are composed of subunits encoded by two closely related genes, acr-26 and acr-27 that are widely distributed in parasitic nematodes infecting humans and animals. We further demonstrate that these receptors represent a molecular target for the anthelmintics morantel and pyrantel. The H. contortus and P. equorum receptors expressed as transgenes in the nematode model Caenorhabditis elegans both confer morantel and pyrantel sensitivity in-vivo. For parasitic nematodes of veterinary and medical importance, this novel class of cholinergic receptor is of prime interest for target-based drug screening and the development of relevant anthelmintic combinations.
1553-7366
Courtot, Elise
26996726-8a53-489a-9c46-63873f48c4f6
Charvet, Claude L.
c0436a6e-8e1a-4073-9cbf-c3d3c5df25a1
Beech, Robin N.
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Harmache, Abdallah
a30da77c-6385-47a6-ba7a-d191d7f631fd
Wolstenholme, Adrian J.
1b90606b-053e-408e-95a8-8b4f3dee75be
Holden-Dye, Linda
8032bf60-5db6-40cb-b71c-ddda9d212c8e
O'Connor, Vincent
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Peineau, Nicolas
bf18553b-36ed-41c0-86c0-90ef677d967b
Woods, Debra J.
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Neveu, Cedric
e982e088-7835-4ba6-ad49-8c4949781c78
Courtot, Elise
26996726-8a53-489a-9c46-63873f48c4f6
Charvet, Claude L.
c0436a6e-8e1a-4073-9cbf-c3d3c5df25a1
Beech, Robin N.
dff8610f-f1d9-4c07-9f1c-c012319808eb
Harmache, Abdallah
a30da77c-6385-47a6-ba7a-d191d7f631fd
Wolstenholme, Adrian J.
1b90606b-053e-408e-95a8-8b4f3dee75be
Holden-Dye, Linda
8032bf60-5db6-40cb-b71c-ddda9d212c8e
O'Connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca
Peineau, Nicolas
bf18553b-36ed-41c0-86c0-90ef677d967b
Woods, Debra J.
0ea8c6a2-4075-414d-843b-11d2d061b8c6
Neveu, Cedric
e982e088-7835-4ba6-ad49-8c4949781c78

Courtot, Elise, Charvet, Claude L., Beech, Robin N., Harmache, Abdallah, Wolstenholme, Adrian J., Holden-Dye, Linda, O'Connor, Vincent, Peineau, Nicolas, Woods, Debra J. and Neveu, Cedric (2015) Functional characterization of a novel class of morantel-sensitive acetylcholine receptors in nematodes. PLoS Pathogens, 11 (12). (doi:10.1371/journal.ppat.1005267).

Record type: Article

Abstract

The control of parasitic nematode infections in humans, livestock and companion animals is critically dependent on anthelmintic treatment. However, the indiscriminate use of anthelmintic drugs has inevitably led to the selection of resistant parasites. In this respect there is currently an urgent need to increase our knowledge of the mode of action of available anthelmintics as well as to identify novel targets for the development of next generation anthelmintic compounds. In the present study we report the functional and pharmacological characterization of a novel subtype of nematode acetylcholine-gated ion channel in two distantly related parasitic nematode species: Haemonchus contortus and Parascaris equorum. Using the Xenopus laevis oocyte as an expression system, we showed that these receptors are composed of subunits encoded by two closely related genes, acr-26 and acr-27 that are widely distributed in parasitic nematodes infecting humans and animals. We further demonstrate that these receptors represent a molecular target for the anthelmintics morantel and pyrantel. The H. contortus and P. equorum receptors expressed as transgenes in the nematode model Caenorhabditis elegans both confer morantel and pyrantel sensitivity in-vivo. For parasitic nematodes of veterinary and medical importance, this novel class of cholinergic receptor is of prime interest for target-based drug screening and the development of relevant anthelmintic combinations.

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Accepted/In Press date: 20 October 2015
Published date: 1 December 2015
Organisations: Biomedicine

Identifiers

Local EPrints ID: 410781
URI: https://eprints.soton.ac.uk/id/eprint/410781
ISSN: 1553-7366
PURE UUID: e945190e-dd09-4eca-8c09-99a6d2dd3a2b

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Date deposited: 09 Jun 2017 09:38
Last modified: 13 Mar 2019 20:07

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Contributors

Author: Elise Courtot
Author: Claude L. Charvet
Author: Robin N. Beech
Author: Abdallah Harmache
Author: Adrian J. Wolstenholme
Author: Nicolas Peineau
Author: Debra J. Woods
Author: Cedric Neveu

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